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Chronic Lymphocytic Leukemia
Paolo Ghia
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CLL – Biology
CLL - Clinical
5 + 40 (1 oral + 2 poster sessions)
5 + 21 (1 oral + 1 poster session)
Number of abstractsTopics
Lunch Debate CLL: are novel prognostic
biomarkers ready for prime time?
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CLL: are novel prognostic biomarkers ready for prime time?
NO! Yes!
Gianluca Gaidano Kostas Stamatopoulos
Università Piemonte Orientale Institute of Applied BiosciencesA. Avogadro CERTH, Thessaloniki
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NOTCH(NOTCH1)
Splicing(SF3B1)
NF-κB(BIRC3)
Wang et al, NEJM 2011; Quesada, Nature Genetics
2011; Puente qt, Nature, 2011; Fabbri et el, JEM 2011
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TP53 M
17p-
TP53 M /17p-
Wt
TP53 abnormalities
30/318=9.4%Wt (n=277; nr)
TP53 M (n=14; 30.2 mo)
17p- (n=16; 19.2 mo)
TP53 M
17p-
TP53 M /17p-
Wt
TP53 abnormalities
46/520=8.8%
GCLLSG CLL4 UK LRF CLL4
Months
OS OS
Wt (n=474)
TP53 M (n=13)17p- (n=8)
TP53 M/17p- (n=25)
5’ 3’
1 DNA BINDING
EX4 EX9
393
Missense Nonsense Frameshift
TP53
Years
TP53 mutations are an independent and robust
predictor of treatment failure in clinical trials
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Happy with p53 aberrations only?
Yes
A. True predictor and not only prognosticator
B. Availability of “overcoming” treatment options
C. More frequent than initially thought
Not reallyA. Infrequent at diagnosis – identifies a particularly aggressive MINORITY
B. DOES NOT explain more than 50% of refractory CLL
C. Things are advancing after all!
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FCR
FC
Therapy:
NOTCH1:
wild type
mutated
Stilgenbauer et al. ASH 2012, Abstract 433
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CLL: MRD as a Surrogate Endpoint for Clinical Trials
White Oak – February 27, 2013
Dreger P et al. Blood 2013 Schnaiter A et al. Blood 2013
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SIMULTANEOUS SESSION
CLL an related disorders: Cinical II
DISEASE PROGRESSION ON IBRUTINIB THERAPY IS UNCOMMON AND IS
ASSOCIATED WITH THE ACQUISITION OF RESISTANCE MUTATIONS: A SINGLE
CENTER EXPERIENCE OF 267 PATIENTS (Maddocks, Columbus)
EFFICACY OF IDELALISIB IN CLL SUBPOPULATIONS HARBORING DEL(17P) AND
OTHER ADVERSE PROGNOSTIC FACTORS: RESULTS FROM A PHASE 3,
RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL (Stilgenbauer,
Ulm)
IBRUTINIB INTERFERES WITH THE CELL-MEDIATED ANTI-TUMOUR ACTIVITIES
OF THERAPEUTIC CD20 ANTIBODIES: IMPLICATIONS FOR COMBINATION
THERAPY (Da Roit, Bergamo)
PHASE 2 STUDY OF THE BTK INHIBITOR IBRUTINIB IN GENETIC RISK-STRATIFIED
RELAPSED AND REFRACTORY PATIENTS WITH CHRONIC LYMPHOCYTIC
LEUKEMIA (CLL)/SMALL LYMPHOCYTIC LYMPHOMA (SLL) (Maddocks, Columbus)
SF3B1 MUTATIONS AND OUTCOME IN CLL PATIENTS TREATED WITH
CHLORAMBUCIL (CHL) OR OFATUMUMAB-CHL (O+CHL): RESULTS FROM THE
PHASE III STUDY COMPLEMENT 1 (Tausch, Ulm)
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OMB110911CHL vs CHL + OFA
SF3B1mut was associated with high WBC, male sex, absence of NOTCH1mut and showed a trend to
absence of +12q and 17p-
SF3B1mut significantly associated with shorter PFS in univariate analysis but not in multivariable analysis
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SIMULTANEOUS SESSION
CLL and related disorders – Biological
ACQUIRED INITIATING MUTATIONS IN EARLY HEMATOPOIETIC CELLS OF
CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS (Damm, Villejuif)
SF3B1 MUTATIONS INDUCE COMMON AND LINEAGE SPECIFIC ABERRANT
MESSENGER RNA SPLICING IN MALIGNANCIES INCLUDING CHRONIC
LYMPHOCYTIC LEUKEMIA AND CONFER SENSITIVITY TO SPLICEOSOME
INHIBITION (Buonamici, Cambridge, US)
IL23 RECEPTOR (IL23R) IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL):
MODULATION, MICRORNA (MIRNA) REGULATION AND PREDICTION POWER. A
PROSPECTIVE MULTICENTER O-CLL STUDY (Morabito, Cosenza)
ISOTYPE MATTERS: FUNCTIONAL DIFFERENCES AFTER SIGM VERSUS SIGD
TRIGGERING OF THE BCR IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL (ten
Hacken, Houston)
CLL INDUCES SEVERE SKEWING IN THE MYELOID COMPARTMENT IN
PATIENTS AND IN THE TCL1 MOUSE MODEL (Hanna, Heidelberg)
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Kikushige Y et al., Cancer Cell 2011
HSC in CLL patients generate Clonal B cells
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Gene
AA
change Chr CD3+ CD14+
CD5+/
CD19+ CD56+
CD34+/
CD19-
Peripheral
neutrophils
CD19+/CD5-
κ+/λ-
CD19+/CD5-
κ-/λ+
CD34+
derived
colony
frequency
BRAF G469R chr7 11% 24% 50% 29% 8% 14% 48% 9% 51/212 = 24%
NOTCH1 P2515Rfs chr9 - 6% 50% - - - 49% - 5/96 = 5%
DSP T1220I chr6 - - 45% - - - 49% - nd
DMGDH E295K chr5 - - 42% - - - 36% - nd
FBP1 V66M chr9 - - 44% - - - 44% - nd
WDR85 A46V chr9 - - 44% - - - 20% - nd
IRS4 S1091N chrX - - 44% - - - 29% - nd
ODZ1 T1109A chrX - - 47% - - - 30% - nd
SNX8 G306S chr7 - - 19% - - - 14% - nd
ADAD2 C268X chr16 - - 31% - - - 32% - nd
C11orf57 E84K chr11 - - 24% - - - 15% - nd
CCDC113 R127W chr16 - - 22% - - - 21% - nd
KIAA1244 C647S chr6 - - 18% - - - 17% - nd
PCDHA5 S290T chr5 - - 17% - - - 16% - nd
RAG1 R737H chr11 - - 16% - - - 13% - nd
Acquired mutations in HSC of CLL patients
Damm et al., CLL Biology Session EHA 2014
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Mutated CD34+ progenitors differentiate into both
lymphoid and myeloid cells
14/24 CLL (58%)
CLL09
0%
10%
20%
30%
40%
50%
60%
0 1 2 3 4 5CD3 CD14 CD34 CD19
Damm et al., CLL Biology Session EHA 2014
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SIMULTANEOUS SESSION
CLL and related disorders – Biological
ACQUIRED INITIATING MUTATIONS IN EARLY HEMATOPOIETIC CELLS OF
CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS (Damm, Villejuif)
SF3B1 MUTATIONS INDUCE COMMON AND LINEAGE SPECIFIC ABERRANT
MESSENGER RNA SPLICING IN MALIGNANCIES INCLUDING CHRONIC
LYMPHOCYTIC LEUKEMIA AND CONFER SENSITIVITY TO SPLICEOSOME
INHIBITION (Buonamici, Cambridge, US)
IL23 RECEPTOR (IL23R) IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL):
MODULATION, MICRORNA (MIRNA) REGULATION AND PREDICTION POWER. A
PROSPECTIVE MULTICENTER O-CLL STUDY (Morabito, Cosenza)
ISOTYPE MATTERS: FUNCTIONAL DIFFERENCES AFTER SIGM VERSUS SIGD
TRIGGERING OF THE BCR IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL (ten
Hacken, Houston)
CLL INDUCES SEVERE SKEWING IN THE MYELOID COMPARTMENT IN
PATIENTS AND IN THE TCL1 MOUSE MODEL (Hanna, Heidelberg)
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Common events
CLL-specific
Breast-specificMelanoma-specific
SF3B1 mutations lead to aberrant splice events
Buonamici et al., CLL Biology Session EHA 2014
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Expression of SF3B1MUT upregulates mutant associated
splice isoforms
a-HA
a-GAPDH
a-SF3B1
a-GAPDH
K6
66
E
K6
66
N
H6
62
Q
K7
00
E
G7
42
D
WT
K7
00
E+R
10
74
H
Vec
tor
con
tro
l
R6
25
C
R6
25
H
E62
2D
SF3B1 cDNA
293FT cells transfected with SF3B1 cDNA
Total RNA extracted for Nanostring
48hr
No
tra
nsf
ecti
on
Expression of WT and MUT isoforms (Nanostring assay)
SF3B1MUT
Buonamici et al., CLL Biology Session EHA 2014
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SIMULTANEOUS SESSION
CLL and related disorders: Cinical 1
ABT-199 (GDC-0199) IN RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC
LEUKEMIA AND SMALL LYMPHOCYTIC LYMPHOMA: HIGH RESPONSE RATES
AMONG PATIENTS WITH HIGH RISK DISEASE FEATURES INCLUDING UNMUTATED
IGHV) (Seymour, Melbourne)
ABT-199 (GDC-0199) COMBINED WITH RITUXIMAB (R) IN PATIENTS (PTS) WITH
RELAPSED / REFRACTORY (R/R) CHRONIC LYMPHOCYTIC LEUKEMIA (CLL):
INTERIM RESULTS OF A PHASE 1B STUDY (Roberts, Melbourne)
SECOND INTERIM ANALYSIS OF A PHASE 3 STUDY EVALUATING IDELALISIB
AND RITUXIMAB FOR RELAPSED CLL (Coutre, Stanford)
A PHASE I STUDY OF THE ORAL BTK INHIBITOR ONO-4059 IN PATIENTS WITH
RELAPSED/REFRACTORY AND HIGH RISK CHRONIC LYMPHOCYTIC LEUKAEMIA
(CLL) (Fegan, Cardiff)
THE ADDITION OF CD20 MONOCLONAL ANTIBODY TO LENALIDOMIDE
IMPROVES RESPONSE RATE AND SURVIVAL IN RELAPSED/REFRACTORY
PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (Thompson, Houston)
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SIMULTANEOUS SESSION
CLL an related disorders: Cinical II
DISEASE PROGRESSION ON IBRUTINIB THERAPY IS UNCOMMON AND IS
ASSOCIATED WITH THE ACQUISITION OF RESISTANCE MUTATIONS: A SINGLE
CENTER EXPERIENCE OF 267 PATIENTS (Maddocks, Columbus)
EFFICACY OF IDELALISIB IN CLL SUBPOPULATIONS HARBORING DEL(17P) AND
OTHER ADVERSE PROGNOSTIC FACTORS: RESULTS FROM A PHASE 3,
RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL (Stilgenbauer,
Ulm)
IBRUTINIB INTERFERES WITH THE CELL-MEDIATED ANTI-TUMOUR ACTIVITIES
OF THERAPEUTIC CD20 ANTIBODIES: IMPLICATIONS FOR COMBINATION
THERAPY (Da Roit, Bergamo)
PHASE 2 STUDY OF THE BTK INHIBITOR IBRUTINIB IN GENETIC RISK-STRATIFIED
RELAPSED AND REFRACTORY PATIENTS WITH CHRONIC LYMPHOCYTIC
LEUKEMIA (CLL)/SMALL LYMPHOCYTIC LYMPHOMA (SLL) (Maddocks, Columbus)
SF3B1 MUTATIONS AND OUTCOME IN CLL PATIENTS TREATED WITH
CHLORAMBUCIL (CHL) OR OFATUMUMAB-CHL (O+CHL): RESULTS FROM THE
PHASE III STUDY COMPLEMENT 1 (Tausch, Ulm)
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PI3K
p85
CD19
Igb
Iga
PIP3
IP3
Ca++
Sintesi proteica
Trascrizione
DAG
ERCa++
Ca++
Grb2ShcBCAP
PI3K
p100δ
BLNK/SLP65
BtkSyk
Bimp1
MALT1
BCL10
PKCβ
AKT
mTORIKK
PLC-γ2
Calcineurin
NFκB
NFκB
NFAT
NFAT
IκB
Lyn
Fostamatinib
Idelalisib
Ibrutinib
BCR
TLR
IRAK4
IRAK1
TRAF6
TAK1
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Randomized Comparison of Ibrutinib Versus Ofatumumab In Previously Treated Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma: Results From The Phase Iii Pcyc-1112 Resonate(tm) Trial
#S693 - Presidential Symposium - Saturday 14th June at 15:00 - Room Gold (SW - Level 2)
ted in NEJM1
1. Byrd JC et al. N Engl J Med 2014; DOI:10.1056/NEJMoa1400376
mPFS: not yet reached (ibrutinib) vs. 8.1 months (ofatumumab) (HR 0.22, P<0.001)
6-month PFS (ibrutinib) 88%
OS: HR 0.43, P<0.005
12-month OS: 90% (ibrutinib) vs. 81% (ofatumumab)
ORR: 42.6% (ibrutinib) vs. 4.1% (ofatumumab) (P<0.001)
An additional 20% of ibrutinib-treated patients had PR with lymphocytosis
Similar efficacy in del17p patients and patients with resistance to purine
The most frequent non-hematologic AEs included diarrhea, fatigue, pyrexia, and nausea
Bleeding-related AEs (any grade) occurred in 44% (ibrutinib) vs. 12% (ofatumumab)
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SIMULTANEOUS SESSION
CLL an related disorders: Cinical II
DISEASE PROGRESSION ON IBRUTINIB THERAPY IS UNCOMMON AND IS
ASSOCIATED WITH THE ACQUISITION OF RESISTANCE MUTATIONS: A SINGLE
CENTER EXPERIENCE OF 267 PATIENTS (Maddocks, Columbus)
EFFICACY OF IDELALISIB IN CLL SUBPOPULATIONS HARBORING DEL(17P) AND
OTHER ADVERSE PROGNOSTIC FACTORS: RESULTS FROM A PHASE 3,
RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL (Stilgenbauer,
Ulm)
IBRUTINIB INTERFERES WITH THE CELL-MEDIATED ANTI-TUMOUR ACTIVITIES
OF THERAPEUTIC CD20 ANTIBODIES: IMPLICATIONS FOR COMBINATION
THERAPY (Da Roit, Bergamo)
PHASE 2 STUDY OF THE BTK INHIBITOR IBRUTINIB IN GENETIC RISK-STRATIFIED
RELAPSED AND REFRACTORY PATIENTS WITH CHRONIC LYMPHOCYTIC
LEUKEMIA (CLL)/SMALL LYMPHOCYTIC LYMPHOMA (SLL) (Maddocks, Columbus)
SF3B1 MUTATIONS AND OUTCOME IN CLL PATIENTS TREATED WITH
CHLORAMBUCIL (CHL) OR OFATUMUMAB-CHL (O+CHL): RESULTS FROM THE
PHASE III STUDY COMPLEMENT 1 (Tausch, Ulm)
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SIMULTANEOUS SESSION
CLL an related disorders: Cinical II
DISEASE PROGRESSION ON IBRUTINIB THERAPY IS UNCOMMON AND IS
ASSOCIATED WITH THE ACQUISITION OF RESISTANCE MUTATIONS: A SINGLE
CENTER EXPERIENCE OF 267 PATIENTS (Maddocks, Columbus)
EFFICACY OF IDELALISIB IN CLL SUBPOPULATIONS HARBORING DEL(17P) AND
OTHER ADVERSE PROGNOSTIC FACTORS: RESULTS FROM A PHASE 3,
RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL (Stilgenbauer,
Ulm)
IBRUTINIB INTERFERES WITH THE CELL-MEDIATED ANTI-TUMOUR ACTIVITIES
OF THERAPEUTIC CD20 ANTIBODIES: IMPLICATIONS FOR COMBINATION
THERAPY (Da Roit, Bergamo)
PHASE 2 STUDY OF THE BTK INHIBITOR IBRUTINIB IN GENETIC RISK-STRATIFIED
RELAPSED AND REFRACTORY PATIENTS WITH CHRONIC LYMPHOCYTIC
LEUKEMIA (CLL)/SMALL LYMPHOCYTIC LYMPHOMA (SLL) (Maddocks, Columbus)
SF3B1 MUTATIONS AND OUTCOME IN CLL PATIENTS TREATED WITH
CHLORAMBUCIL (CHL) OR OFATUMUMAB-CHL (O+CHL): RESULTS FROM THE
PHASE III STUDY COMPLEMENT 1 (Tausch, Ulm)
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SIMULTANEOUS SESSION
CLL an related disorders: Cinical II
DISEASE PROGRESSION ON IBRUTINIB THERAPY IS UNCOMMON AND IS
ASSOCIATED WITH THE ACQUISITION OF RESISTANCE MUTATIONS: A SINGLE
CENTER EXPERIENCE OF 267 PATIENTS (Maddocks, Columbus)
EFFICACY OF IDELALISIB IN CLL SUBPOPULATIONS HARBORING DEL(17P) AND
OTHER ADVERSE PROGNOSTIC FACTORS: RESULTS FROM A PHASE 3,
RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL (Stilgenbauer,
Ulm)
IBRUTINIB INTERFERES WITH THE CELL-MEDIATED ANTI-TUMOUR ACTIVITIES
OF THERAPEUTIC CD20 ANTIBODIES: IMPLICATIONS FOR COMBINATION
THERAPY (Da Roit, Bergamo)
PHASE 2 STUDY OF THE BTK INHIBITOR IBRUTINIB IN GENETIC RISK-STRATIFIED
RELAPSED AND REFRACTORY PATIENTS WITH CHRONIC LYMPHOCYTIC
LEUKEMIA (CLL)/SMALL LYMPHOCYTIC LYMPHOMA (SLL) (Maddocks, Columbus)
SF3B1 MUTATIONS AND OUTCOME IN CLL PATIENTS TREATED WITH
CHLORAMBUCIL (CHL) OR OFATUMUMAB-CHL (O+CHL): RESULTS FROM THE
PHASE III STUDY COMPLEMENT 1 (Tausch, Ulm)
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Ibrutinib inhibits NK activation and ADCC at doses reached in vivo
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Ibrutinib inhibits phagocytosis of CLL by macrophages in vivo
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Ibrutinib inhibits nuetrophils activation and phagocytosis
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Comparison between Ibrutinib and Idelalisib
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Burger et al, Lancet Oncol 2014
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Burger et al, Lancet Oncol 2014
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SIMULTANEOUS SESSION
CLL and related disorders: Cinical 1
ABT-199 (GDC-0199) IN RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC
LEUKEMIA AND SMALL LYMPHOCYTIC LYMPHOMA: HIGH RESPONSE RATES
AMONG PATIENTS WITH HIGH RISK DISEASE FEATURES INCLUDING UNMUTATED
IGHV) (Seymour, Melbourne)
ABT-199 (GDC-0199) COMBINED WITH RITUXIMAB (R) IN PATIENTS (PTS) WITH
RELAPSED / REFRACTORY (R/R) CHRONIC LYMPHOCYTIC LEUKEMIA (CLL):
INTERIM RESULTS OF A PHASE 1B STUDY (Roberts, Melbourne)
SECOND INTERIM ANALYSIS OF A PHASE 3 STUDY EVALUATING IDELALISIB
AND RITUXIMAB FOR RELAPSED CLL (Coutre, Stanford)
A PHASE I STUDY OF THE ORAL BTK INHIBITOR ONO-4059 IN PATIENTS WITH
RELAPSED/REFRACTORY AND HIGH RISK CHRONIC LYMPHOCYTIC LEUKAEMIA
(CLL) (Fegan, Cardiff)
THE ADDITION OF CD20 MONOCLONAL ANTIBODY TO LENALIDOMIDE
IMPROVES RESPONSE RATE AND SURVIVAL IN RELAPSED/REFRACTORY
PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (Thompson, Houston)
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Study 116: Randomized, Double-Blind, Placebo-Controlled
Idelalisib (150 mg BID)
Placebo (BID)
Rituximab (6 months)
Dis
ease
Pro
gre
ssi
on
Scre
en
Double-BlindInitial Therapy Blinded Dose Open-Label
Extension Study 117
Idelalisib (150 mg BID)
Idelalisib (300 mg BID)
Interim Analyses and Unblinding
Blinded, Independent
Review
Double-BlindContinuous
Therapy
• Primary Endpoint: PFS; Secondary: ORR, LNR, OS
• Interim analyses (IAs) planned at 50% and 75% of total events,
DMC recommended early study stop after 1st IA (Furman et al., NEJM 2014)
• 2nd IA conducted at end of the blinded-phase according to amendment
(data cut-off 09 October 2013 with 63% of total PFS events)
Rituximab (6 months)
Randomizationand Stratification
Primary Study 116
Independent Review
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Lymph Node Response
45
-1 0 0
-7 5
-5 0
-2 5
0
2 5
5 0
7 5
1 0 0
1 2 5
Be
st
% C
ha
ng
e i
n S
PD
Id e la lis ib + R itu x im a b
n = 1 0 2a
P la c e b o + R itu x im a b
n = 1 0 1a
aE v a lu a b le p a t ie n t s
D e l(1 7 p ) a n d / o r T P 5 3 m u t
N e it h e r D e l(1 7 p ) o r T P 5 3 m u t
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Primary Endpoint: PFS
46
0 2 4 6 8 1 0 1 2 1 4 1 6 1 80
2 0
4 0
6 0
8 0
1 0 0
Pro
gre
ss
ion
-fre
e S
urv
iva
l (%
)
Id e la lis ib + R it u x im a b
M e d ia n P F S : N o t r e a c h e d
P la c e b o + R it u x im a b
M e d ia n P F S : 5 .5 m o n t h s
Id e la lis ib + R 1 1 0 (0 ) 8 7 (3 ) 5 4 (7 ) 3 5 (8 ) 3 0 (1 0 ) 1 7 (1 4 ) 7 (1 5 ) 2 (1 6 ) 1 (1 6 ) 0 (1 6 )
P la c e b o + R 1 1 0 (0 ) 6 9 (2 1 ) 3 7 (3 7 ) 1 9 (4 4 ) 1 4 (4 9 ) 6 (5 4 ) 3 (5 6 ) 1 (5 8 ) 0 (5 9 ) 0 (5 9 )
T im e (M o n th s )N a t r is k (E v e n t s )
H R = 0 .1 8 ,
9 5 % C I (0 .1 0 , 0 .3 2 ),
P < 0 .0 0 0 1
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SAE, n (%) IDELA + R (N=110) Placebo + R (N=108)
Patients with any SAE 54 (49) 41 (38)Pneumonia 10 (9) 11 (10)Pyrexia 10 (9) 3 (3)Febrile neutropenia 5 (5) 5 (5)Sepsis 5 (5) 3 (3)Pneumonitis 4 (4) 1 (1)Pneum. jirov. pneumonia 3 (3) 1 (1)Diarrhea 3 (3) 0Hypercalcemia 2 (2) 2 (2)Abdominal pain 2 (2) 1 (1)Hypoxia 2 (2) 1 (1)Colitis 2 (2) 0Deep vein thrombosis 2 (2) 0Sepsis syndrome 2 (2) 0Neutropenia 2 (2) 0Neutropenic sepsis 2 (2) 0Lung infection 2 (2) 0Transient ischemic attack 2 (2) 0
47* Occurring in ≥2 patients on IDELA + R
Serious Adverse Events (SAEs)*
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Category, n (%)IDELA + R (N=110) Placebo + R (N=108)
Any Gr. Gr. 3/4 Any Gr. Gr. 3/4
Anemia 32 (29) 8 (7) 35 (32) 18 (17)
Neutropenia 66 (60) 41 (37) 55 (51) 29 (27)
Thrombocytopenia 21 (19) 12 (11) 34 (32) 19 (18)
ALT/AST elevation* 44 (40) 9 (8) 22 (20) 1 (1)
Laboratory Abnormalities of Interest
48
* 7 of the 9 patients in the IDELA + R arm were successfully re-challenged:
• 3 at 150 mg BID, 4 at the reduced dose of 100 mg BID
• One patient’s transaminase elevation was associated with CLL transformation (Richter) in the
liver (progressive disease).
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SIMULTANEOUS SESSION
CLL an related disorders: Cinical II
DISEASE PROGRESSION ON IBRUTINIB THERAPY IS UNCOMMON AND IS
ASSOCIATED WITH THE ACQUISITION OF RESISTANCE MUTATIONS: A SINGLE
CENTER EXPERIENCE OF 267 PATIENTS (Maddocks, Columbus)
EFFICACY OF IDELALISIB IN CLL SUBPOPULATIONS HARBORING DEL(17P) AND
OTHER ADVERSE PROGNOSTIC FACTORS: RESULTS FROM A PHASE 3,
RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL (Stilgenbauer,
Ulm)
IBRUTINIB INTERFERES WITH THE CELL-MEDIATED ANTI-TUMOUR ACTIVITIES
OF THERAPEUTIC CD20 ANTIBODIES: IMPLICATIONS FOR COMBINATION
THERAPY (Da Roit, Bergamo)
PHASE 2 STUDY OF THE BTK INHIBITOR IBRUTINIB IN GENETIC RISK-STRATIFIED
RELAPSED AND REFRACTORY PATIENTS WITH CHRONIC LYMPHOCYTIC
LEUKEMIA (CLL)/SMALL LYMPHOCYTIC LYMPHOMA (SLL) (Maddocks, Columbus)
SF3B1 MUTATIONS AND OUTCOME IN CLL PATIENTS TREATED WITH
CHLORAMBUCIL (CHL) OR OFATUMUMAB-CHL (O+CHL): RESULTS FROM THE
PHASE III STUDY COMPLEMENT 1 (Tausch, Ulm)
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ORR In Subpopulations
50
Favors
Control
Favors
Treatmen
t
* No subjects in the control arm reached the overall response status of CR or PR as of date of analysis
** All subjects in the treatment arm reached the overall response status of CR or PR as of date of analysis
Subgroup OR 95%CI
IDELA+R PLACEBO+R
n ORR(%) n ORR(%)
Overall 29.92 12.76,70.11 88 80.7 88 12.5
del(17p)positive* NA NA,NA 20 80.0 24 0.00
del(17p)negative 21.01 8.46,52.18 68 80.9 64 17.2
TP53mutationpositive 41.51 8.12,212.26 34 79.4 30 10.0
TP53mutationnegative 23.16 8.57,62.60 54 81.5 58 13.8
Bothdel(17p)andTP53mutation* NA NA,NA 17 76.5 15 0.00
Eitherdel(17p)orTP53mutation 48.00 7.23,318.84 20 85.0 24 12.5
Neitherdel(17p)norTP53mutation 20.46 7.31,57.26 51 80.4 49 16.3
del(11q)positive 175.82 11.48,2692.29 28 78.6 29 6.9
del(11q)negative 22.03 8.27,58.69 57 82.5 59 15.3
IGHVmutated 62.92 5.79,683.55 17 88.2 16 12.5
IGHVunmutated 26.36 10.52,66.06 71 78.9 72 12.5
ZAP70positive 28.73 11.33,72.85 77 79.2 75 13.3
ZAP70negative** NA NA,NA 8 100.0 12 8.3
CD38positive 29.27 7.67,111.65 43 83.7 34 17.6
CD38negative 30.32 9.57,96.09 44 77.3 54 9.3
ß2-microglobulin:<=4mg/L** NA NA,NA 12 100.0 18 16.7
ß2-microglobulin:>4mg/L 23.13 9.24,57.89 74 77.0 68 11.8
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Del(17p): Best Nodal Response
51
-1 0 0
-7 5
-5 0
-2 5
0
2 5
5 0
7 5
1 0 0
1 2 5
Be
st
% C
ha
ng
e i
n S
PD ID E L A + R it u x im a b P la c e b o + R it u x im a b
N o d e l(1 7 p ) (n = 6 2 )
d e l(1 7 p ) (n = 2 2 )
N o d e l(1 7 p ) (n = 6 7 )
d e l(1 7 p ) (n = 1 8 )
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Subgroup HR 95%CI
IDELA+R PLACEBO+R
n PFS n PFS
Overall 0.15 0.08,0.28 110 NR 110 5.5
del(17p)positive 0.14 0.04,0.47 26 NR 31 3.7
del(17p)negative 0.14 0.07,0.31 84 NR 79 6.5
TP53mutationpositive 0.11 0.04,0.31 42 NR 39 3.8
TP53mutationnegative 0.15 0.06,0.37 68 NR 71 7.1
Bothdel(17p)andTP53mutation 0.13 0.04,0.47 22 NR 21 3.5
Eitherdel(17p)orTP53mutation 0.09 0.02,0.42 24 NR 28 5.6
Neitherdel(17p)norTP53mutation 0.17 0.07,0.43 64 NR 61 7.1
del(11q)positive 0.16 0.05,0.59 36 NR 32 6.9
del(11q)negative 0.14 0.07,0.31 71 NR 75 5.5
IGHVmutated 0.25 0.07,0.95 19 12.1 17 11.1
IGHVunmutated 0.13 0.06,0.27 91 NR 93 5.0
ZAP70positive 0.13 0.06,0.25 98 NR 93 5.0
ZAP70negative* NA NA,NA 9 NR 16 8.3
CD38positive 0.13 0.05,0.34 62 NR 51 6.9
CD38negative 0.13 0.05,0.34 47 NR 59 5.5
ß2-microglobulin:<=4mg/L* NA NA,NA 16 NR 24 11.1
ß2-microglobulin:>4mg/L 0.14 0.07,0.27 92 NR 81 3.8
PFS In Subpopulations
52
Favors
Control
Favors
Treatmen
t
* Subjects in the treatment arm are 100% censored as of date of analysis
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Del(17p): PFS
Idelalisib
+
Rituxima
b
Placebo
+
Rituxima
b
No 17p- (n=84)
No 17p- (n=79)
17p- (n=26)
17p- (n=31)
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Del(17p) and/or TP53 mutations: PFS
54
Idelalisib
+
Rituxima
b
Placebo
+
Rituxima
b
Either 17p- or
TP53mut
(n=24)
Either 17p- or
TP53mut
(n=28)
Both 17p- and
TP53mut (n=22)
Both 17p- and
TP53mut
(n=21)
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Del(11q): PFS
55
Idelalisib
+
Rituxima
b
Placebo
+
Rituxima
b
No 11q- (n=71)
No 11q-
(n=75)
11q-
(n=36)
11q-
(n=32)
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IGHV Mutation Status: PFS
Idelalisib
+
Rituxima
b
Placebo
+
Rituxima
b
IGHV mut
(n=19)
IGHV mut
(n=17)
IGHV unmut
(n=91)
IGHV unmut (n=93)
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β2-Microglobulin: PFS
Idelalisib
+
Rituxima
b
Placebo
+
Rituxima
b
ß2-M ≤ 4 mg/L
(n=16)
ß2-M ≤ 4 mg/L
(n=24)
ß2-M > 4 mg/L
(n=92)
ß2-M > 4 mg/L
(n=81)
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SIMULTANEOUS SESSION
CLL and related disorders: Cinical 1
ABT-199 (GDC-0199) IN RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC
LEUKEMIA AND SMALL LYMPHOCYTIC LYMPHOMA: HIGH RESPONSE RATES
AMONG PATIENTS WITH HIGH RISK DISEASE FEATURES INCLUDING UNMUTATED
IGHV) (Seymour, Melbourne)
ABT-199 (GDC-0199) COMBINED WITH RITUXIMAB (R) IN PATIENTS (PTS) WITH
RELAPSED / REFRACTORY (R/R) CHRONIC LYMPHOCYTIC LEUKEMIA (CLL):
INTERIM RESULTS OF A PHASE 1B STUDY (Roberts, Melbourne)
SECOND INTERIM ANALYSIS OF A PHASE 3 STUDY EVALUATING IDELALISIB
AND RITUXIMAB FOR RELAPSED CLL (Coutre, Stanford)
A PHASE I STUDY OF THE ORAL BTK INHIBITOR ONO-4059 IN PATIENTS WITH
RELAPSED/REFRACTORY AND HIGH RISK CHRONIC LYMPHOCYTIC LEUKAEMIA
(CLL) (Fegan, Cardiff)
THE ADDITION OF CD20 MONOCLONAL ANTIBODY TO LENALIDOMIDE
IMPROVES RESPONSE RATE AND SURVIVAL IN RELAPSED/REFRACTORY
PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (Thompson, Houston)
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59
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QUESTIONS
2. How would you choose between the new inhibitors?
3. How would you treat a CLL patients in first line?
1. Can we have easier names for the new drugs?1. Should the new genetic mutations be included in the
work-up before treatment?
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CLL: MRD as a Surrogate Endpoint for Clinical Trials
White Oak – February 27, 2013
THE END
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SIMULTANEOUS SESSION
Novel CLL genetics – Clinical implications
ACQUIRED INITIATING MUTATIONS IN EARLY HEMATOPOIETIC CELLS
OF CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS (Damm, Villejuif)
SF3B1 MUTATIONS INDUCE COMMON AND LINEAGE SPECIFIC
ABERRANT MESSENGER RNA SPLICING IN MALIGNANCIES INCLUDING
CHRONIC LYMPHOCYTIC LEUKEMIA AND CONFER SENSITIVITY TO
SPLICEOSOME INHIBITION (Buonamici, Cambridge, US)
IL23 RECEPTOR (IL23R) IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL):
MODULATION, MICRORNA (MIRNA) REGULATION AND PREDICTION
POWER. A PROSPECTIVE MULTICENTER O-CLL STUDY (Morabito,
Cosenza)
ISOTYPE MATTERS: FUNCTIONAL DIFFERENCES AFTER SIGM VERSUS
SIGD TRIGGERING OF THE BCR IN CHRONIC LYMPHOCYTIC LEUKEMIA
(CLL (ten Hacken, Houston)
CLL INDUCES SEVERE SKEWING IN THE MYELOID COMPARTMENT IN
PATIENTS AND IN THE TCL1 MOUSE MODEL (Hanna, Heidelberg)
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CLL induces T cell abnormalities including an impaired
immunological synapse
Ramsay A. ERIC Symposium EHA 2014; JCI, 2010; Ramsay et al, Blood 2012
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T cell
a-CD3/a-CD28
CLL cell
T cell
T cell
T cell
a-CD3/a-CD28
T cell
T cell
T cell proliferation measured by CFSEDilution Assay
Primary human cells
Eµ-TCL1
Suppressive activity of CLL monocytes
CFSE
% o
f m
ax
T cells alone
PBS
Anti-CD3/CD28
T-cells alone
T-cells + monos 1:1
1:2 Monos : T cells
T-cells alone
T-cells +
monos 1:2
1:1 Monos : T cells
Seiffert M, ERIC Symposium, EHA 2014; Hanna et al, CLL Biology Session EHA 2014; Jitschin e al, Blood 2014
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